TARGETED MUCOSAL VACCINES AGAINST HIV 1

本项目的主要目标是提高抗体和T细胞 HIV-1粘膜亚单位疫苗的反应。为了实现这一目标，我们 使用大肠杆菌不耐热肠毒素（LT）靶向嵌合体， HIV-1蛋白粘附于粘膜表面。 因为没有一个被接受的 保护性免疫的相关性，我们的研究将追求细胞 以及粘膜免疫后的体液反应。 为了增加T 细胞反应，我们已经开发出系统，以取代LT的片段， HIV-1蛋白的表位，以便选择性地递送这些表位。 决定因素的细胞质区室，相交的类 I MHC抗原加工途径。 这些嵌合体的能力 将评估在该途径中诱导和引发反应的蛋白质 在小鼠和猴模型中，特别强调 这些反应会激活分泌β-趋化因子的T细胞。 此外，本发明还提供了一种方法， 我们开发了一种新的真核表达系统， LT-Env嵌合体的正确折叠，预期其引起有效的 粘膜免疫后的中和抗体反应。这些嵌合体 将在鼠和猴模型中进行评价，重点是 诱导中和HIV-1原代分离株的抗体。

The principal goal of this project is to enhance antibody and T cell responses to HIV-1 mucosal subunit vaccines. To achieve this goal, we are using the Escherichia coil heat-labile enterotoxin (LT) to target chimeric HIV-1 proteins to mucosal surfaces. Because there is no single accepted correlate of protective immunity, our studies will pursue both cellular and humoral responses that follow from mucosal immunization. To augment T cell responses, we have developed systems to replace segments of LT with epitopes of HIV-1 proteins in order to selectively deliver these determinants to the cytoplasmic compartment that intersects with the Class I MHC antigen processing pathway. The abilities of these chimeric proteins to induce and elicit responses in this pathway will be evaluated in murine and monkey models, with special emphasis being placed on responses that call up T cells that secrete beta-chemokines. In addition, we have developed a novel eukaryotic expression system that allows the proper folding of LT-Env chimeras that are expected to elicit potent neutralizing antibody responses after mucosal immunization. These chimeras will be evaluated in murine and monkey models with emphasis on the induction of antibodies that neutralize primary isolates of HIV-1.